Based on our understanding of envelope-based mechanisms of humoral evasion, we have attempted to design envelope-based immunogens with these mechanisms disabled. Such modied immunogens with weakened defenses may elicit more broadly neutralizing antibodies. We have also devised protein scaffolding technologies, as a means of presenting structural mimics of the epitopes of broadly neutralizing antibodies to assist in their re-elicitation. Scaffolds can be non-homologous proteins, identified through structural searches of the entire Protein Data Bank (PDB). Alternatively, scaffolds can be homologous proteins, which are structurally similar, but antigenically distinct from the HIV-1 envelope glycoproteins. An alternative to scaffolding involves resurfacing, where the surface of a molecule, not involved in eliciting a desired response, is altered between prime and boost phases of immunization. We have also been investigating how insights from B cell ontogeny of broadly neutralizing antibodies identifies difficult steps in the elicitation process, which might be influenced by immunization; related antibody-lineage based design is also being explored. Finally, work with the fusion glycoprotein from respiratory syncytial virus (RSV) indicates that it is important to focus on a site rather than an epitope, and perhaps best to focus on an overall conformation. One important criterion is whether the site and conformation are sensitive to neutralization. Such a neutralization-sensitve site paradigm is allowing for positive vaccine results against RSV and may be useful against HIV-1, influenza A virus, and other global pathogens. A related paradigm of vaccine design involve epitope-focusing.